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Twenty years on: the impact of fragments on drug discovery
Abstract
After 20 years of sometimes quiet growth, fragment-based drug discovery (FBDD) has become mainstream. More than 30 drug candidates derived from fragments have entered the clinic, with two approved and several more in advanced trials. FBDD has been widely applied in both academia and industry, as evidenced by the large number of papers from universities, non-profit research institutions, biotechnology companies and pharmaceutical companies. Moreover, FBDD draws on a diverse range of disciplines, from biochemistry and biophysics to computational and medicinal chemistry. As the promise of FBDD strategies becomes increasingly realized, now is an opportune time to draw lessons and point the way to the future. This Review briefly discusses how to design fragment libraries, how to select screening techniques and how to make the most of information gleaned from them. It also shows how concepts from FBDD have permeated and enhanced drug discovery efforts.
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“Fragment-based ligand discovery (FBLD) has emerged as a versatile approach for the discovery of atom-efficient, small-molecule binders for a wide range of proteins10–12.”
From Expedited mapping of the ligandable proteome using fully functionalized enantiomeric probe pairs (2019) · cites this paper as [12]
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X-Ray Crystallography of Viruses
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The future of covalent inhibition
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Self-citationTransforming Drug Discovery and Development:The Impact of Artificial Intelligence
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Identification of a Novel Subtype-Selective α1B-Adrenoceptor Antagonist
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Self-citationIntroduction to Computer-Based Simulations and Methodologies in Pharmaceutical Research
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The rise of NMR-integrated fragment-based drug discovery in China
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Structural Biology for Target Identification and Validation
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NMR-Based Fragment Screen of the von Hippel-Lindau Elongin C&B Complex
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Fragment-based discovery enables direct targeting of the melanoma oncogene MITF
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“Fragment screening is a well-established approach to identify chemical starting points and novel binding sites 16 .”
Self-citationProtein crystallization strategies in structure-based drug design
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“This issue is even more pronounced in fragment-based lead generation (FBLG) approaches [73] where initial hits often are very weak binders.”
Targeting PTPN22 at Nonorthosteric Binding Sites─A Fragment Approach
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“64 Despite these key advantages, obtaining crystal structures of the primary fragment hits in complex with the target protein remains a major hurdle for fragment-based drug discovery campaigns.”
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HiFrAMes: A Framework for Hierarchical Fragmentation and Abstraction of Molecular Graphs
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“In fragment-based drug discovery (FBDD), fragments are commonly described as low complexity molecules with molecular weight below 300 Da and typically no more than 20 heavy atoms (non-hydrogen atoms) [26–28].”
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Metadata
- Authors
- Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H.
- Affiliations
- Carmot Therapeutics (United States) (US)
- Vanderbilt University (US)
- Vernalis (R&D) Limited (United Kingdom) (GB)
- Novartis (Switzerland) (CH)
- Corresponding author
- Erlanson, Daniel A.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2016-07-15
- Volume
- 15
- Issue
- 9
- Pages
- 605-619
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- OpenAlex
- W2467779447
- Cited by
- 1,000
- References
- 110
- Citations by year
- 2026: 80 · 2025: 92 · 2024: 112 · 2023: 95 · 2022: 97 · 2021: 106 · 2020: 141 · 2019: 79 · 2018: 99 · 2017: 84 · 2016: 14
- FWCI
- 7.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- fragment-based drug discovery, fragment libraries, fragment screening
- MeSH terms
- Clinical Trials as Topic, Humans, Peptide Fragments, Protein Conformation, Peptide Library, Computational Biology, Small Molecule Libraries, Drug Discovery, High-Throughput Screening Assays
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